1. Field of the Invention
This invention relates generally to compositions having utility for the treatment of vaginal yeast while promoting normal bacterial growth, and to a method of treatment of vaginal yeast conditions.
2. Description of the Related Art
Yeast infections, also termed Candidiasis, moniliasis, or Monilia vaginitis, are among the most frequently occurring of vaginal infections. These vaginal infections are caused by fungus-like yeasts of the genus Candida (formerly Monilia), and specifically the species including C. albicans, C. tropicalis, C. psuedotropicalis, and C. stellatoidea. These Candida fungal microorganisms, also known as Monilia, normally grow and thrive at low concentrations in the mouth, gastrointestinal tract, and vagina, coexisting with the normal biological flora in these regions, without adverse effect on health or physiological function.
In the vagina, the homeostasis between these Candida fungi and the normal vaginal flora nonetheless may be upset by changes in vaginal pH, or other conditions upsetting the vaginal equilibrium or otherwise lowering resistance to infection. Monilia overgrowth then may occur, resulting in a thick, white colored vaginal discharge which often is likened to cottage cheese in consistency, and associated with a strong odor. This condition occurs frequently in women during pregnancy, or as a result of conditions such as diabetes, treatment with antibiotics, steroids or immunosuppressive therapy, or hormonal changes occurring during the menstrual cycle.
The two major classes of antifungal agents employed are the polyenes (nystatin and amphotericin) and the imidazole derivatives (miconazole, clotrimazole, butuconazole, and ketoconazole).
Over the counter preparations for vaginal cleaning and deodorization generally contain glacial acetic acid and water and may contain glycerin and various thickening agents. Although vinegar douches comprising a solution of vinegar and water have been commonly employed for many years for cosmetic douching purposes, and are often resorted to for flushing yeast deposits and bacteria from the Monilia-infected vagina, such methods do not in fact destroy the Candida fungi in situ. The pH of these products are all at or below 3.5 when measured on a pH meter. The normal vaginal pH is approximately 4.5 and this homeostatic condition is not significantly altered by vinegar douching. Vinegar douching treatment has been predicated on the incorrect belief that lower pH values in the vagina promote the growth of normal vaginal flora at the expense of Candidal fungal species. In the vaginal pH range, the pathogenic yeasts compete with normal bacterial flora, displacing or suppressing the growth of biota needed for healthy vaginal functioning.
More effective treatment of Candida infections typically involves the application of an anti-yeast medication to the vagina, with intravaginal administration of medicine being repeated at selected intervals over a period of days or weeks.
An example of an intravaginally applied medication is a water miscible cream composition containing 2% by weight 1-2,4-dichloro-beta-(2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate in a cream base comprising mineral oil, pegoxol-7 stearate, peglicol-5-oleate, butylated hydroxyanisole, benzoic acid, and water, commercially available from Ortho Pharmaceutical Corporation, Raritan, N.J., under the trademark MONISTAT 7. This composition is recommended by the manufacturer to be applied intravaginally once daily for 7 days.
It is an object of the present invention to provide a Candidastatic and/or Candidacidal composition which promotes a high rate of growth of normal vaginal biota during treatment, while selectively inhibiting the growth, reproduction and germination of Candida organisms in the vagina.
Other compositions used to treat Candida, and other uses for the components or related components of Applicant's composition are discussed below.
U.S. Defensive Publication T937,002 of N. G. Baker discloses the treatment of ungulate mastitis, a bacterial infection, with glycols having 3 to 4 carbon atoms and at least one terminal group, e.g., 1,3-butylene glycol, administered in pharmacologically effective doses. The disclosure of this reference and of all others cited herein is incorporated herein by reference.
U.S. Pat. No. 4,310,510 to K. N. Sherman, et al. discloses an intravaginally applied anti-fertility composition comprising a foamable aqueous emulsion containing progesterone as the active ingredient. The Sherman, et al. patent at column 8, lines 48-68 discloses that the formulation, in addition to progesterone and an anionic surfactant, may contain buffering agents such as phosphates, citrates or tartrates, to maintain a pH in the range normal in the female genital tract, that is on the order of about 4.5 in the vagina. In a preferred disclosed embodiment, the composition contains 10-50% by weight of a lower glycol as a foam stabilizer, the patent stating that in such concentration range, the glycols prevent microbial growth in the formulation so that preservatives are not required. In addition, other foam stabilizers may be substituted for glycols, such as glycerol and the polyalkylene glycols, such as polypropylene glycol and polyglycerols.
Among the progesterone compounds useful in the practice of Sherman's antifertility composition (column 6, lines 11-30 of Sherman) are various progestin acetate compounds. There is no indication in Sherman of any Candidacidal activity of glycols and/or a non-steroid acetate compound nor of their use in the absence of progesterone and anionic surfactants.
U.S. Pat. No. 3,970,759 to J. W. Frankenfeld, et al. discloses the inhibition of bacteria, yeasts, and molds in cosmetic personal care compositions containing edible oils and organic nitrogen compounds, by incorporating therein an effective amount of a linear aliphatic 1,3-diol, or a monoester or diester thereof. The diols disclosed as suitable for this purpose contain 5-15 carbon atoms in the chain; suitable diesters have a linear aliphatic acyl group of 2-20 carbons.
U.S. Pat. No. 4,294,852 to R. H. Wildnauer, et al. discloses a topically applied skin composition for treatment and control of dry skin disorders, comprising an aqueous phase in which is dissolved one or more specified aliphatic alcohols in combination with one or more selected aliphatic mono, di- or tri- carboxylic acids having 2-10 carbon atoms, including those which are substituted at either or both of the alpha and beta carbons with a hydroxyl or keto functional group.
The Wildnauer, et al. patent discloses at column 5, lines 6-7 that the disclosed composition may comprise propylene glycol as an additive. Propylene glycol is also mentioned in the same column at lines 17 et seq. as an active compound with which the disclosed composition may be employed as a vehicle. Other such active ingredients include dexamethasone acetate and anti-fungal agents such as griseofulvin, Mycostatin.TM., miconazole and minconazole nitrate. Among the alpha, beta-dihydroxy carboxylic acids disclosed in the patent are glyceric acid; the disclosed keto acids include glyoxylic acid, pyruvic acid and acetoacetic acid.
U.S. Pat. No. 3,836,672 to D. D. Wright, et al. discloses the treatment of bacterial and fungal infections by linear diols and/or their mono-esters, the diols containing 7-15 carbons and hydroxy groups on the first and third carbon atoms while the mono-esters have acyl groups of 2-10 carbons.
The Wright, et al. patent discloses in the paragraph bridging columns 4 and 5 that Monilial vaginitis caused by Candida albicans is treated to control the fungal organism with minimum disturbance of the normal vaginal bacterial flora. A 50-50 mixture of 1,3-nonanediol and 1,3-butanediol monooctanoate is disclosed as effective for the treatment of fungal vaginitis, and as being effective against fungi at levels where it is only mildly inhibitory to bacteria. The patent at column 6, lines 30-38 describes inert carriers for the disclosed compositions, including glycerol as an inert carrier for providing a paste or cream-like consistency, or propylene glycol or ethylene glycol as an inert carrier for propellant type or aerosol materials.
U.S. Pat. No. 3,821,413 to H. L. Hellyer, Jr., discloses atmospheric germicidal compositions comprising from about 5-85% by weight of a glycol germicide, e.g., ethylene glycol, or propylene glycol, from 2-40% by weight of an organic polar coupling compound including various specified alcohols such as beta-phenylethyl alcohol and alphaterpineol, and from about 5-80% by weight of an organic, relatively non-polar compound for forming hydrophobic micelles surrounding the glycol molecules in the mixture to reduce the glycol affinity to atmospheric moisture. The non-polar compounds disclosed in the patent at column 2, lines 54-58 include various acetate compounds such as benzyl acetate, citronellyl acetate, octyl acetate, and 1,3-nonanediol acetate.
U.S. Pat. No. 3,384,541 to W. G. Clark discloses a spermicidal vaginal foam-producing composition comprising ethoxylated tallow alcohol, propylene glycol or other glycols or glycerol. The patent discloses to utilize such composition in combination with a buffered fructose solution. Example 23 of the patent teaches to add iodine compounds to the composition for the treatment of vaginitis, and Candida albicans, Monilia, and Trichomonas vaginalis, along with the contraceptive function of the composition.
U.S. Pat. No. 2,451,955 to H. Keil, et al. discloses the use of a composition to determine susceptibility to dermatitis, comprising a solution of a synthetic vicinal alkyl pyrocatechol with 10-18 carbons in the alkyl group, in a non-irritant organic solvent such as iso-amyl acetate, a water insoluble acetate ester.
U.S. Pat. No. 2,467,884 to N. N. Elias discloses spermicidal compositions comprising neutral aliphatic hydroxy compounds such as higher fatty alcohols, hydroxyethers, hydroxyesters and hydroxyester ethers. The composition may comprise an aqueous vehicle containing a water soluble acid for bringing the pH of the resulting composition within the range of 1-7. The patent discloses that the pH is established by means of whatever simple organic or inorganic acids and buffer salts may seem desirable. The patent discloses that glycerine may be added to the spermicidal compositions to prevent their dehydration and freezing. The patent also discloses the use of water soluble acids such as acetic acid, with potassium acetate and sodium acetate being disclosed as buffers.
When Saccharomyces yeast cells are incubated in hypertonic glycerol solutions, the cells shrink to about 40% of their original volume with glycerol premeating the cells resulting in alteration of membrane morphology. The shrinking is reversible upon removal from the 8.7% glycerol solution but incubation in solutions above 17.4% glycerol is lethal for exponentially growing yeasts. Protoplasma 92:177 (1977).
Glycerol is also known to be metabolized by yeasts as Candida and Saccharomyces and is a by-product of some yeast metabolism. See European J. Biochem 5:165 (1968).